Antibody: Retinal and Retinal Pigment Epithelium (RPE) Autoimmunity in Age-related Macular Degeneration (AMD)

• Sponsor: Lawrence S. Morse, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00931489
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 131
• Location: 1
• Arms: 5
• Duration (Months): 58
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The investigators hope to determine if "wet" AMD patients differ from patients with "dry" AMD or normal eyes in the production of anti-retinal pigment epithelium (anti-RPE) or anti-retinal antibody formation. To explain: the immune system can make antibodies that attack our own cells, specifically the RPE and the retina. Normally the RPE and retinal cells are ignored by the immune system, but when disease occurs, immune reactions can occur, making an autoantibody that can attack the patient's own cells and make things worse. This production of autoantibodies that react with our own RPE and retinal cells is what the investigators want to test in this proposal to see if they may contribute to, or are responsible for, a poor response to treatment.

The investigators also want to know how those patients who initially respond to the standard-of-care treatment, ranibizumab injections, differ in the production of anti-RPE or anti-retinal antibody formation, from those patients who do not respond initially after 4 consecutive injections.

Condition or Disease	Intervention/Treatment	Phase
Age Related Macular Degeneration	Drug: ranibizumab (Lucentis(R))	Phase 2

Detailed Description

Up to 10% of patients with neovascular AMD treated with ranibizumab respond poorly or worsen despite therapy. The reason for this lack of response is unclear. We have preliminary data that suggests abnormal autoimmune activity is apparent in these patients. Previous studies have shown evidence of retinal autoimmunity in AMD patients, but there is very little data describing any specific immunologic commonality that correlates with disease and/or poor response. (8,9) Perhaps just as significantly there is little data regarding the immunologic activity of age-matched normals, making published data hard to evaluate especially in this age group in which autoimmunity is known to increase. (8,9) While there are many known retinal antigens in autoimmune retinal disease, the role of these antigens is not well established in AMD and not all the antigens have been identified. (24) Moreover, RPE-reactivities are only beginning to be understood in ocular disease. (25-27) We intend to address humoral responses in AMD by making a systematic comparison of the immunologic activity of ranibizumab responders, ranibizumab initial non-responders, and a comparable population of age-sex-race matched normal controls. Data suggests that 5 groups of patients are evident after 3 treatments with ranibizumab: 1) rapid responders, 2) delayed responders, 3) gradual responders, 4) acutenon-responders and 5) chronic non-responders. We hypothesize that non-responders and gradual responders may in fact be patients with complicating underlying autoimmune activity involving retinal and RPE antigens, which are exposed secondary to the breakdown of the blood-retinal barrier during CNV development. We will study this humoral response (antibody production) over the treatment period, as it likely is changing at different rates in the patients with different responses. In addition we will correlate underlying genetic phenotype in these patients.

For this study, we plan to look at 2 treatment groups and 2 control groups:

• Group 1: patients with neovascular AMD who respond to ranibizumab after 4 consecutive injections with ranibizumab

• Group 2: age-sex-race matched normal population controls (without AMD)

• Group 3: patients with neovascular AMD who are acute non-responders to anti-VEGF treatment after 4 or more consecutive injections

• Group 4: age-sex-race matched dry AMD patients (AREDS category 2/3 ou) controls

• Group 5: patients with neovascular AMD who are chronic non-responders to anti-VEGF treatment after 4 or more consecutive injections

This is an open-label study assessing antibody formation (anti-RPE and anti-retinal) in 5 groups. Group 1 (n=40) will include neovascular AMD patients treated with ranibizumab. Patients will be included and receive 4 ranibizumab 0.5mg intravitreally at 4-6 week intervals and then twice more "as needed" (PRN) at 4-6 week intervals. After the 4th ranibizumab injection, if a Group 1 patient has not responded (persistent fluid on OCT), they will be moved into Group 3 (anti-VEGF acute non-responders) or Group 5 (anti-VEGF chronic non-responders). This will reduce the eventual number of subjects enrolled in Group 1 to approximately 36, as we anticipate approximately 4 subjects to have to move to either Group 3 or Group 5 as a non-responder. Group 2 (n=40) will be an age-sex-race matched normal subjects from the population that does not have AMD. Group 3 (n=8) and Group 5 (n=7) (for a combined total of 15 subjects, approximately 4 of whom transferred from Group 1) include patients treated with 4 or more injections of anti-VEGF treatment at 4-8 week intervals without an initial response (Initial non-response is defined as < 100 microns of improved [decreased] retinal thickening by OCT). Group 3 patients, the acute non-responders, will be included after the 4th injection and followed for 2 more visits at 4-8 week intervals during which time they can receive "as needed" anti-VEGF treatment(s) at the investigator's discretion for any fluid on OCT. Group 4 (n=40) will be age-sex-race matched patients with Dry AMD as controls for immune response before there is a neovascular response. Group 5 patients, the chronic non-responders, will be included after the 4th injection and followed for one (1) visit at Month 4 during which time they can receive an "as needed" anti-VEGF treatment at the investigator's discretion for any fluid on OCT.

NOTE: Only 10% of Group 1 (approximately 4 patients) are expected to be non-responders, therefore, 11 of the Group 3 and Group 5 subjects will be patients treated outside the study who are found to be non-responders by chart review. These patients will then be enrolled at the Month 4 visit to supplement the subjects transferred from Group 1 for a total of 15 patients in Groups 3 and 5.

We will use Western blotting for global assessment of all autoantibodies against the full complement of retinal proteins in both normal individuals (Group 2) and those treated for exudative AMD (Group 1), those initial non-responders to ranibizumab (Group 3), and patients with "dry" AMD (Group 4).

Genotyping (CFH and HTRA1) will be performed on all Groups. Approximately 25 ml (2 tablespoons) of blood will be sent to Dr. Khang Zhang of the Shiley Eye Center at the University of California, San Diego and he will perform the genetics analysis.

This study will investigate if antibody production differs between nv AMD patients (Groups 1, 3 and 5) and the normal population (Group 2), if it differs between ranibizumab responders (Group 1) and non-responders to any anti-VEGF treatment (Groups 3 and 5), and we will also see how patients with dry AMD (Group 4) compare with the nv AMD groups (Groups 1, 3, and 5).

Study Design

• Study Type: Interventional
• Actual Enrollment: 131 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Retinal and RPE Autoimmunity in AMD: Assessment of Correlation With Degree of Response to Ranibizumab Therapy
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Wet AMD Patients Responders Dilated eye exam once a month for 7 months; visual acuity and OCT once a month for 7 months; Lucentis(R)/ranibizumab injection once each month for the Baseline and Month 1-3 visits, then as needed at Month 4 and 5; 3 Tbls. blood draw at Baseline, Month 3 and Month 6 visits.	Drug: ranibizumab (Lucentis(R)); 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months; Other Names: Lucentis(R)
No Intervention: Normal Population Dilated eye exam and 3 Tbls. blood draw at first and only study visit.
Active Comparator: Wet AMD Patients Acute Non-responders Participants in this Group will have not responded to 4 prior injections of Lucentis(R)/ranibizumab or other anti-VEGF treatment. Dilated eye exam at Month 4; visual acuity and OCT at Months 4-6; injection of anti-VEGF treatment as needed at Months 4 and 5; 3 Tbls. blood draw at Month 4	Drug: ranibizumab (Lucentis(R)); 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months; Other Names: Lucentis(R)
No Intervention: Dry AMD Population Dilated eye exam and 3 Tbls. blood draw at first and only study visit.
Active Comparator: Wet AMD Patients Chronic Non-responderes Participants in this Group will have not responded to 4 or more prior injections of Lucentis(R)/ranibizumab or other anti-VEGF treatment. One visit at Month 4: Dilated eye exam with visual acuity and OCT; injection of anti-VEGF as needed; 3 Tbls. blood drawn	Drug: ranibizumab (Lucentis(R)); 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months; Other Names: Lucentis(R)

Outcome Measures

Primary Outcome Measures

1. Production of Anti-Retinal Pigment Epithelium (RPE) or Anti-retinal Antibody Formation in Neovascular ("Wet") Age-related Macular Degeneration Patients Compared to Population Normals. [6 months]

   Blood samples were collected from all study participants at baseline and Western Blot analysis was performed to identify the presence of anti-retinal and anti-RPE antibodies. Presented are the number of subjects in which the presence of anti-retinal and anti-RPE antibodies (yes/no) were recorded by a masked observer.

Secondary Outcome Measures

1. Change in Visual Acuity (VA) From Baseline to Month 6 [6 months]

   Subjects visual acuity (VA) was tested using Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Letters correctly read on ETDRS chart was recorded at baseline and 6 months. Mean change was measured.

2. Change in Ocular Coherence Tomography (OCT) From Baseline to Month 6 [6 months]

   Ocular Coherence Tomography (OCT) was used to measure retinal central foveal thickness. The mean change from baseline to 6 months was determined and recorded in micrometers (µm).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Group 1 (Ranibizumab Responders):

• Ability to provide written informed consent and comply with study assessments for the full duration of the study

• Age > 50 years

• Patients with active neovascular "wet" AMD naïve to treatment

• Group 2 (Normal Controls):

• Age-sex-race matched to Group 1 patients

• Non-AMD

• Ability to provide written informed consent

• Group 3 (Anti-VEGF Initial Non-responders):

• "Wet" AMD patient treated with 4 or more monthly injections of anti-VEGF treatment without an adequate response (persistent fluid on OCT)

• Ability to provide written informed consent and comply with study assessments for the full duration of the study

• Age > 50 years

• Group 4 ("Dry" AMD):

• Age-sex-race matched to Group 1 patients

• "Dry" AMD, category 2 or 3 by AREDS (Age-Related Eye Disease Study) criteria

• Ability to provide written informed consent

Exclusion Criteria:

• Pregnancy (positive pregnancy test) or lactation

• Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch.

• Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated

• Participation in another simultaneous medical investigation or trial

• Concurrent eye disease in the study eye that could compromise visual acuity (e.g., diabetic retinopathy, advanced glaucoma)

• Previous AMD therapy

• Patients being treated for autoimmune or other disease with immunomodulatory drugs (i.e., prednisone, infliximab, methotrexate)

• Patients with recent (less than 6 months) ocular or systemic surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Davis	Sacramento	California	United States	95817

Sponsors and Collaborators

• Lawrence S. Morse, MD
• Genentech, Inc.

Investigators

• Principal Investigator: Lawrence S Morse, MD, PhD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lawrence S. Morse, MD, Professor, University of California, Davis
• ClinicalTrials.gov Identifier: NCT00931489
• Other Study ID Numbers: 217330; FVF4479s
• First Posted: Jul 2, 2009
• Last Update Posted: Jul 2, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Lawrence S. Morse, MD, Professor, University of California, Davis: Age Related Macular Degeneration; Lucentis; Ranibizumab; Antibodies; Retinal and RPE Autoimmunity
• Additional relevant MeSH terms: Macular Degeneration; Autoimmune Diseases; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Wet AMD Patients Responders	Normal Population	Wet AMD Patients Acute Non-responders	Dry AMD Population	Wet AMD Patients Chronic Non-responderes
Arm/Group Description	Dilated eye exam once a month for 7 months; visual acuity and OCT once a month for 7 months; Lucentis(R)/ranibizumab injection once each month for the Baseline and Month 1-3 visits, then as needed at Month 4 and 5; 3 Tbls. blood draw at Baseline, Month 3 and Month 6 visits. ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months	Dilated eye exam and 3 Tbls. blood draw at first and only study visit.	Participants in this Group will have not responded to 4 prior injections of Lucentis(R)/ranibizumab or other anti-VEGF treatment. Dilated eye exam at Month 4; visual acuity and OCT at Months 4-6; injection of anti-VEGF treatment as needed at Months 4 and 5; 3 Tbls. blood draw at Month 4 ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months	Dilated eye exam and 3 Tbls. blood draw at first and only study visit.	Participants in this Group will have not responded to 4 or more prior injections of anti-VEGF treatment. One visit at Month 4: Dilated eye exam with visual acuity and OCT; injection of anti-VEGF as needed; 3 Tbls. blood drawn ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months
Period Title: Overall Study
STARTED	40	40	5	39	7
COMPLETED	40	40	5	39	7
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Wet AMD Patients Responders	Normal Population	Wet AMD Patients Acute Non-responders	Dry AMD Population	Wet AMD Patients Chronic Non-responderes	Total
Arm/Group Description	Dilated eye exam once a month for 7 months; visual acuity and OCT once a month for 7 months; Lucentis(R)/ranibizumab injection once each month for the Baseline and Month 1-3 visits, then as needed at Month 4 and 5; 3 Tbls. blood draw at Baseline, Month 3 and Month 6 visits. ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months	Dilated eye exam and 3 Tbls. blood draw at first and only study visit.	Participants in this Group will have not responded to 4 prior injections of Lucentis(R)/ranibizumab or other anti-VEGF treatment. Dilated eye exam at Month 4; visual acuity and OCT at Months 4-6; injection of anti-VEGF treatment as needed at Months 4 and 5; 3 Tbls. blood draw at Month 4 ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months	Dilated eye exam and 3 Tbls. blood draw at first and only study visit.	Participants in this Group will have not responded to 4 or more prior injections of anti-VEGF treatment. One visit at Month 4: Dilated eye exam with visual acuity and OCT; injection of anti-VEGF as needed; 3 Tbls. blood drawn ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months	Total of all reporting groups
Overall Participants	40	40	5	39	7	131
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	80.35 (9.24)	67.82 (7.39)	78.20 (8.41)	77.08 (9.50)	82.86 (8.41)	75.60 (10.15)
Sex: Female, Male (Count of Participants)
Female	24 60%	23 57.5%	3 60%	22 56.4%	3 42.9%	75 57.3%
Male	16 40%	17 42.5%	2 40%	17 43.6%	4 57.1%	56 42.7%

Outcome Measures

1. Primary Outcome

Title	Production of Anti-Retinal Pigment Epithelium (RPE) or Anti-retinal Antibody Formation in Neovascular ("Wet") Age-related Macular Degeneration Patients Compared to Population Normals.
Description	Blood samples were collected from all study participants at baseline and Western Blot analysis was performed to identify the presence of anti-retinal and anti-RPE antibodies. Presented are the number of subjects in which the presence of anti-retinal and anti-RPE antibodies (yes/no) were recorded by a masked observer.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The "wet" AMD patients' 6 month values in production of RPE or anti-retinal antibody formation are being compared to the Normal Population baseline values.

Arm/Group Title	Neovascular "Wet" Age-related Macular Degeneration Patients	Population Normals
Arm/Group Description	Subjects with active neovascular ("wet") AMD. This includes the subjects that responded to treatment (Ranibizumab 0.5mg intravitreal injections at four week intervals) Group 1, and chronic "non-responders" - those subjects who received four or more anti-VEGF intravitreal injections with persistent fluid on OCT, Group 3. At baseline, 40 subjects were enrolled into Group 1 Following 4 months of treatment, 3 subjects were moved to Group 3.	Normals are subjects that do not have Age-related Macular Degeneration. Group 2
Measure Participants	45	40
Baseline	31 77.5%	26 65%
6 Months	36 90%

2. Secondary Outcome

Title	Change in Visual Acuity (VA) From Baseline to Month 6
Description	Subjects visual acuity (VA) was tested using Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Letters correctly read on ETDRS chart was recorded at baseline and 6 months. Mean change was measured.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

At the 6 month timepoint - 3 of the 40 subjects enrolled into Group 1 (Wet AMD responders) had been moved to Group 3 due to persistent subretinal fluid on OCT (protocol definition of "non-responder" following 4 months of treatment).

Arm/Group Title	Neovascular "Wet" AMD Patients - Responders	Neovascular "Wet" AMD Patients - Acute Non-responders
Arm/Group Description	Subjects with neovascular ("wet") Age-related Macular Degeneration who respond to ranibizumab after 4 consecutive intraocular injections Group 1	Subjects with neovascular ("wet") AMD treated with 4 or more monthly injections of anti-VEGF without an adequate response (persistent fluid on OCT) Group 3 - non-responders
Measure Participants	37	8
Mean (Full Range) [letters gained]	10.08	6.14

3. Secondary Outcome

Title	Change in Ocular Coherence Tomography (OCT) From Baseline to Month 6
Description	Ocular Coherence Tomography (OCT) was used to measure retinal central foveal thickness. The mean change from baseline to 6 months was determined and recorded in micrometers (µm).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

At the 6 month timepoint - 3 of the 40 subjects enrolled into Group 1 (Wet AMD responders) had been moved to Group 3 due to persistent subretinal fluid on OCT (protocol definition of "non-responder" following 4 months of treatment).

Arm/Group Title	Neovascular "Wet" AMD Patients - Responders	Neovascular "Wet" AMD Patients - Acute Non-responders
Arm/Group Description	Subjects with neovascular ("wet") Age-related Macular Degeneration who respond to ranibizumab after 4 consecutive intraocular injections Group 1	Subjects with neovascular ("wet") AMD treated with 4 or more monthly injections of anti-VEGF without an adequate response (persistent fluid on OCT) Group 3 - non-responders
Measure Participants	37	8
Mean (Full Range) [µm]	-82	22

Adverse Events

Time Frame	6 months
Arm/Group Title	Wet AMD Patients Responders		Normal Population		Wet AMD Patients Acute Non-responders		Dry AMD Population		Wet AMD Patients Chronic Non-responderes
Arm/Group Description	Dilated eye exam once a month for 7 months; visual acuity and OCT once a month for 7 months; Lucentis(R)/ranibizumab injection once each month for the Baseline and Month 1-3 visits, then as needed at Month 4 and 5; 3 Tbls. blood draw at Baseline, Month 3 and Month 6 visits. ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months		Dilated eye exam and 3 Tbls. blood draw at first and only study visit.		Participants in this Group will have not responded to 4 prior injections of Lucentis(R)/ranibizumab or other anti-VEGF treatment. Dilated eye exam at Month 4; visual acuity and OCT at Months 4-6; injection of anti-VEGF treatment as needed at Months 4 and 5; 3 Tbls. blood draw at Month 4 ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months		Dilated eye exam and 3 Tbls. blood draw at first and only study visit.		Participants in this Group will have not responded to 4 or more prior injections of anti-VEGF treatment. One visit at Month 4: Dilated eye exam with visual acuity and OCT; injection of anti-VEGF as needed; 3 Tbls. blood drawn ranibizumab (Lucentis(R)): 0.5 mg intravitreal injection once a month for 4 months, then as needed for 2 months
All Cause Mortality
	Wet AMD Patients Responders		Normal Population		Wet AMD Patients Acute Non-responders		Dry AMD Population		Wet AMD Patients Chronic Non-responderes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Wet AMD Patients Responders		Normal Population		Wet AMD Patients Acute Non-responders		Dry AMD Population		Wet AMD Patients Chronic Non-responderes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)		0/40 (0%)		0/5 (0%)		0/40 (0%)		0/7 (0%)
Eye disorders
Uveitis	1/40 (2.5%)	1	0/40 (0%)	0	0/5 (0%)	0	0/40 (0%)	0	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Wet AMD Patients Responders		Normal Population		Wet AMD Patients Acute Non-responders		Dry AMD Population		Wet AMD Patients Chronic Non-responderes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)		0/5 (0%)		0/40 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.